Synthetic Biology Journal ›› 2023, Vol. 4 ›› Issue (3): 444-463.DOI: 10.12211/2096-8280.2023-003
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Zhi SUN1, Ning YANG1, Chunbo LOU2, Chao TANG1, Xiaojing YANG1
Received:
2023-01-02
Revised:
2023-02-09
Online:
2023-07-05
Published:
2023-06-30
Contact:
Chao TANG, Xiaojing YANG
孙智1, 杨宁1, 娄春波2, 汤超1, 杨晓静1
通讯作者:
汤超,杨晓静
作者简介:
基金资助:
CLC Number:
Zhi SUN, Ning YANG, Chunbo LOU, Chao TANG, Xiaojing YANG. Rational design for functional topology and its applications in synthetic biology[J]. Synthetic Biology Journal, 2023, 4(3): 444-463.
孙智, 杨宁, 娄春波, 汤超, 杨晓静. 功能拓扑的理性设计及其在合成生物学中的应用[J]. 合成生物学, 2023, 4(3): 444-463.
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URL: https://synbioj.cip.com.cn/EN/10.12211/2096-8280.2023-003
Fig. 1 Rational design for biological networks(a) Identification of biological functions. (b) Two typical design methods: enumeration and optimization. (c) Workflow for these methods. Enumeration method: determining ODE (ordinary differential equation) according to reaction types, randomly sampling parameters to simulate ODE, and finally filtering topological networks with their functions as criteria. Optimization method: describing ODE by neural network to optimize the error function, and finally obtaining the topological networks by knockout experiments. (d) Determination of the final topological networks
功能 | 表型 | 拓扑 | 备注 |
---|---|---|---|
适应性 | 酶促反应网络 Me, et al., 2009[ | ||
振荡 | Wagner, 2005[ Elowitz and Leibler, 2000[ | ||
双稳态 | Shah and Sarkar, 2011[ | ||
持续性检测 | Alon, 2007[ | ||
抗噪 | Nie, et al., 2020[ | ||
体节发育 | Ma, et al., 2006[ | ||
细胞极化 | Chau,et al., 2012[ | ||
适应性/振荡双功能 | Zhang, et al., 2019[ | ||
调频/调幅响应 | 转录调控网络 Gao, et al., 2018[ |
Table 1 Typical functional topology developed theoretically
功能 | 表型 | 拓扑 | 备注 |
---|---|---|---|
适应性 | 酶促反应网络 Me, et al., 2009[ | ||
振荡 | Wagner, 2005[ Elowitz and Leibler, 2000[ | ||
双稳态 | Shah and Sarkar, 2011[ | ||
持续性检测 | Alon, 2007[ | ||
抗噪 | Nie, et al., 2020[ | ||
体节发育 | Ma, et al., 2006[ | ||
细胞极化 | Chau,et al., 2012[ | ||
适应性/振荡双功能 | Zhang, et al., 2019[ | ||
调频/调幅响应 | 转录调控网络 Gao, et al., 2018[ |
线路类型 | 节点数/设计层次 | 拓扑结构/线路特点 | 可执行功能 | 主要基因元件或模块 |
---|---|---|---|---|
基本转录调控线路 | 单节点 | 自抑制 | 降低表达噪声; 加速响应完成时间; 剂量响应线性化 | TetR自抑制;aTc剂量效应[ TetR自抑制结合光感元件LOV2响应光强度剂量[ |
自激活 | 双稳态自维持; “双模态”切换动力学; 参数分岔的“磁滞现象” | DBD-VP64自激活,pGal-DBD-VP64记忆瞬时乳糖浓度[ ZF-VP64自激活,响应多种瞬时刺激[ rtTA自激活线路,测试切换动力学[ tTA-VP16自激活,红霉素响应元件E-KRAB调控[ σ因子SigW自激活,利用RsiW调谐“磁滞区间”[ | ||
双节点 | “互抑制”型正反馈 | 双稳态自维持; “双模态”切换动力学; 参数分岔的“磁滞现象” | LacⅠ与CI构建toggle switch拨动开关[ RecA裂解CI控制双稳态切换,控制TraA表达诱发生物膜[ 利用mfLon蛋白酶控制拨动开关[ 利用UAS与pGal设计主开关,控制toggle switch开启[ PIP/E-KRAB构建toggle switch[ TALE元件设计toggle switch,耦联TALE自激活线路[ 正交TALE元件库,shRNA控制拨动开关,细胞分类器[ 定量RBS折叠自由能可预测设计toggle switch二态比例[ | |
“激活-抑制”型负反馈 | 内源性自主振荡; 受迫振荡; “锁相”行为; 适应性响应 | LacⅠ-AraC,节点间负反馈结合自调控,设计自主振荡[ 温敏LacⅠ,补偿LacⅠ-AraC振荡线路的温度变化影响[ LacⅠ-AraC,周期性外源Arabinose驱动下的“锁相”振荡[ sense/anti-sense mRNA或siRNA设计负反馈振荡[ T7 RNAP与CRISPRi/dCpf1设计正负反馈耦合,实现RPA[ | ||
多节点 | 负反馈环路 | 三节点互抑制振荡 | TetR-LacⅠ-λCI的三节点互抑制负反馈环[ TetR-LacⅠ-λCI的三节点负反馈环简化,实现超稳定振荡[ 微流与光阱捕获技术,线路建库,筛选稳定振荡菌株[ | |
前馈线路 | 脉冲发生器(iFFL); 带通滤波器(iFFL); 信号加速器(cFFL) | 天然系统中的前馈实现信号加速与延迟的理论分析[ AHL扩散,LuxR-CI-GFP构建iFFL实现pulse generator[ LuxR-CI-GFP iFFL的空间动力学行为[ 光感pompC-LuxI-CI控制下游pLux-λ构建iFFL,边界探测[ tTA-Pip-E-KRAB构建iFFL,响应aTc剂量的band-pass filter[ 转录元件精确定量表征,构建iFFL的定量可预测设计[ | ||
组合逻辑线路 | 各类逻辑门线路 | 利用TetR-LacⅠ-λCI元件设计一系列逻辑门线路[ 双启动子控制阻遏蛋白的NOR Gate基本框架[ TetR family的正交NOT Gate阻遏蛋白挖掘[ | ||
时序逻辑线路 | 触点开关; 条件记忆学习线路; 锁存器线路 | LexA-LacⅠ NOR Gate,CI-CI434双稳态,组合构建触点开关[ tag-supD AND Gate、CI-CI434双稳态,巴甫洛夫样学习线路[ 双稳态与NOR Gate组合锁存结构,时序切换控制[ | ||
集成基因线路 | 多节点 | 组合前馈逻辑线路 | 逻辑门线路自动化设计; 逻辑切换动力学预测; 个性化线路设计 | Cello实现基因线路三输入逻辑真值表自动化CAD设计[ 四输入自动化设计,动力学过程表征与预测[ 基因组上Landing Pad超稳定低负载基因线路CAD设计[ 非模式菌的基础元件表征与线路CAD设计[ S. cerevisiae的基础元件设计表征与线路CAD设计[ |
多层次调控线路 | DNA层次 | 重组酶线路 | 带通滤波器; 表达顺序控制线路 | Bxb1、φC31、TP901重组酶受H2O2浓度调控,构建iFFL[ Cre、Flp、φC31受GIB、ABA诱导二聚化的自移除设计[ |
RNA层次 | RNA元件 | RNA结合蛋白; RNA Replicon系统 | L7Ae、MS2结合蛋白的互抑制设计,RNA Replicon双稳态[ 使用TMP-DHFR可诱导降解标签调控L7Ae结合蛋白浓度[ | |
CRISPR Circuit | CRISPR/Cas元件设计; Cas主蛋白中枢型线路 | TetR-CI-CRISPR/dCas9构建repressilator[ CRISPR/dCas9的转录抑制调控元件设计与表征[ dCas9*-PhlF融合构建减毒CRISPR调控系统[ 以dCas9、dCas12a为中枢蛋白设计的sgRNA调控线路等[ | ||
蛋白质层次 | 蛋白酶线路 | 降解肽切割调控; 分裂蛋白多聚化调控 | TEV/TVMV/SuMMV Protease移除/暴露降解肽标签调控设计[ Split TEV/TVMV/HCV Protease调控结合leucine zipper二聚化调控,设计logic gate、iFFL、protease toggle等功能[ | |
转录因子互作 | 多稳态基因调控线路 | GCN4、FKBP等结构域调控ZF结合蛋白二聚化多稳态线路[ | ||
翻译后修饰 | 超快速响应切换线路 | CRE1/STAT5设计磷酸化OR Gate,PTP-pHOG1对HOT1-pJH1去磷酸化NOT Gate,组合设计信号转导toggle switch[ | ||
鲁棒性控制线路 | 模块间“追溯活性” | 线路问题检查 | 负载表达动力学干扰; 元件模块化组装干扰 | pLac与lacO负载位点对LacⅠ的竞争,干扰表达动力学[ LuxR-NahR-GFP顺序组装后系统行为偏离预期[ |
功能修复线路 | 转录因子磷酸化线路; 激酶/磷酸酶元件开发; 减弱资源竞争模块设计; 公共资源自调节线路 | NRII(L16R)-NRII(H139N),STAT5-HKRR/ EnvZ激酶/磷酸酶活性改造,对OmpR-VP64调控活性控制,磷酸化水平负反馈线路控制表达[ ECF32 σ因子表达sRNA-mRNA负反馈;CasE切割mRNA 5′-UTR、miR-FF4设计iFFL线路等,减弱资源竞争效应[ 设计sgRNA靶向dCas9的自负反馈,公共中枢蛋白资源表达自调节,减弱下游模块间竞争[ | ||
“线路-底盘”互作 | 线路问题检查 | 拓扑对生长的敏感性; 资源占用导致生长停滞 | AraC自激活与TetR-LacI互抑制对生长速率的不同敏感性[ pT7-T7 RNAP的自激活线路产生显著的表达量-生长异质性[ | |
功能修复线路 | 低拷贝基因线路设计; 表达负担负反馈线路; 毒性转录因子自负反馈; 生长速率补偿调控 | 基因组单拷贝整合的TetR-LacⅠ toggle switch[ 负担敏感phtpG1控制CRISPR/dCas9抑制的负反馈控制[ 转录因子CymR的自抑制诱导系统设计,减弱生长抑制毒性[ SpoTH元件降低ppGpp含量,维持生长速率恒定[ | ||
扰动噪声屏蔽 | 目的基因表达控制 | 稳定基因拷贝数变异; 组合iFFL/负反馈线路 | TALE设计线性抑制功能,稳定启动子表达受拷贝数影响[ rtTA-LacI/miR-FF3设计iFFL,排除转染量影响[ tTA-miR-FF4的iFFL与负反馈,组合控制[ | |
积分反馈控制线路 | σ/anti-σ; sense/anti-sense mRNA | SigW-RsiW的σ/anti-σ互作设计积分反馈控制[ tTA sense/anti-sense mRNA互作设计反馈控制[ | ||
鲁棒性功能拓扑发掘 | 基于拓扑约束的线路构建与扰动测试 | 基于拓扑穷举理论计算结果,T7 RNAP与CRISPR/dCpf1设计负反馈耦合线性弱自激活的基因线路,在输入信号改变、拓扑参数变异及底盘生理条件等进行系统扰动下均可实现RPA功能[ |
Table 2 Functional topology that has been constructed and used in synthetic biology
线路类型 | 节点数/设计层次 | 拓扑结构/线路特点 | 可执行功能 | 主要基因元件或模块 |
---|---|---|---|---|
基本转录调控线路 | 单节点 | 自抑制 | 降低表达噪声; 加速响应完成时间; 剂量响应线性化 | TetR自抑制;aTc剂量效应[ TetR自抑制结合光感元件LOV2响应光强度剂量[ |
自激活 | 双稳态自维持; “双模态”切换动力学; 参数分岔的“磁滞现象” | DBD-VP64自激活,pGal-DBD-VP64记忆瞬时乳糖浓度[ ZF-VP64自激活,响应多种瞬时刺激[ rtTA自激活线路,测试切换动力学[ tTA-VP16自激活,红霉素响应元件E-KRAB调控[ σ因子SigW自激活,利用RsiW调谐“磁滞区间”[ | ||
双节点 | “互抑制”型正反馈 | 双稳态自维持; “双模态”切换动力学; 参数分岔的“磁滞现象” | LacⅠ与CI构建toggle switch拨动开关[ RecA裂解CI控制双稳态切换,控制TraA表达诱发生物膜[ 利用mfLon蛋白酶控制拨动开关[ 利用UAS与pGal设计主开关,控制toggle switch开启[ PIP/E-KRAB构建toggle switch[ TALE元件设计toggle switch,耦联TALE自激活线路[ 正交TALE元件库,shRNA控制拨动开关,细胞分类器[ 定量RBS折叠自由能可预测设计toggle switch二态比例[ | |
“激活-抑制”型负反馈 | 内源性自主振荡; 受迫振荡; “锁相”行为; 适应性响应 | LacⅠ-AraC,节点间负反馈结合自调控,设计自主振荡[ 温敏LacⅠ,补偿LacⅠ-AraC振荡线路的温度变化影响[ LacⅠ-AraC,周期性外源Arabinose驱动下的“锁相”振荡[ sense/anti-sense mRNA或siRNA设计负反馈振荡[ T7 RNAP与CRISPRi/dCpf1设计正负反馈耦合,实现RPA[ | ||
多节点 | 负反馈环路 | 三节点互抑制振荡 | TetR-LacⅠ-λCI的三节点互抑制负反馈环[ TetR-LacⅠ-λCI的三节点负反馈环简化,实现超稳定振荡[ 微流与光阱捕获技术,线路建库,筛选稳定振荡菌株[ | |
前馈线路 | 脉冲发生器(iFFL); 带通滤波器(iFFL); 信号加速器(cFFL) | 天然系统中的前馈实现信号加速与延迟的理论分析[ AHL扩散,LuxR-CI-GFP构建iFFL实现pulse generator[ LuxR-CI-GFP iFFL的空间动力学行为[ 光感pompC-LuxI-CI控制下游pLux-λ构建iFFL,边界探测[ tTA-Pip-E-KRAB构建iFFL,响应aTc剂量的band-pass filter[ 转录元件精确定量表征,构建iFFL的定量可预测设计[ | ||
组合逻辑线路 | 各类逻辑门线路 | 利用TetR-LacⅠ-λCI元件设计一系列逻辑门线路[ 双启动子控制阻遏蛋白的NOR Gate基本框架[ TetR family的正交NOT Gate阻遏蛋白挖掘[ | ||
时序逻辑线路 | 触点开关; 条件记忆学习线路; 锁存器线路 | LexA-LacⅠ NOR Gate,CI-CI434双稳态,组合构建触点开关[ tag-supD AND Gate、CI-CI434双稳态,巴甫洛夫样学习线路[ 双稳态与NOR Gate组合锁存结构,时序切换控制[ | ||
集成基因线路 | 多节点 | 组合前馈逻辑线路 | 逻辑门线路自动化设计; 逻辑切换动力学预测; 个性化线路设计 | Cello实现基因线路三输入逻辑真值表自动化CAD设计[ 四输入自动化设计,动力学过程表征与预测[ 基因组上Landing Pad超稳定低负载基因线路CAD设计[ 非模式菌的基础元件表征与线路CAD设计[ S. cerevisiae的基础元件设计表征与线路CAD设计[ |
多层次调控线路 | DNA层次 | 重组酶线路 | 带通滤波器; 表达顺序控制线路 | Bxb1、φC31、TP901重组酶受H2O2浓度调控,构建iFFL[ Cre、Flp、φC31受GIB、ABA诱导二聚化的自移除设计[ |
RNA层次 | RNA元件 | RNA结合蛋白; RNA Replicon系统 | L7Ae、MS2结合蛋白的互抑制设计,RNA Replicon双稳态[ 使用TMP-DHFR可诱导降解标签调控L7Ae结合蛋白浓度[ | |
CRISPR Circuit | CRISPR/Cas元件设计; Cas主蛋白中枢型线路 | TetR-CI-CRISPR/dCas9构建repressilator[ CRISPR/dCas9的转录抑制调控元件设计与表征[ dCas9*-PhlF融合构建减毒CRISPR调控系统[ 以dCas9、dCas12a为中枢蛋白设计的sgRNA调控线路等[ | ||
蛋白质层次 | 蛋白酶线路 | 降解肽切割调控; 分裂蛋白多聚化调控 | TEV/TVMV/SuMMV Protease移除/暴露降解肽标签调控设计[ Split TEV/TVMV/HCV Protease调控结合leucine zipper二聚化调控,设计logic gate、iFFL、protease toggle等功能[ | |
转录因子互作 | 多稳态基因调控线路 | GCN4、FKBP等结构域调控ZF结合蛋白二聚化多稳态线路[ | ||
翻译后修饰 | 超快速响应切换线路 | CRE1/STAT5设计磷酸化OR Gate,PTP-pHOG1对HOT1-pJH1去磷酸化NOT Gate,组合设计信号转导toggle switch[ | ||
鲁棒性控制线路 | 模块间“追溯活性” | 线路问题检查 | 负载表达动力学干扰; 元件模块化组装干扰 | pLac与lacO负载位点对LacⅠ的竞争,干扰表达动力学[ LuxR-NahR-GFP顺序组装后系统行为偏离预期[ |
功能修复线路 | 转录因子磷酸化线路; 激酶/磷酸酶元件开发; 减弱资源竞争模块设计; 公共资源自调节线路 | NRII(L16R)-NRII(H139N),STAT5-HKRR/ EnvZ激酶/磷酸酶活性改造,对OmpR-VP64调控活性控制,磷酸化水平负反馈线路控制表达[ ECF32 σ因子表达sRNA-mRNA负反馈;CasE切割mRNA 5′-UTR、miR-FF4设计iFFL线路等,减弱资源竞争效应[ 设计sgRNA靶向dCas9的自负反馈,公共中枢蛋白资源表达自调节,减弱下游模块间竞争[ | ||
“线路-底盘”互作 | 线路问题检查 | 拓扑对生长的敏感性; 资源占用导致生长停滞 | AraC自激活与TetR-LacI互抑制对生长速率的不同敏感性[ pT7-T7 RNAP的自激活线路产生显著的表达量-生长异质性[ | |
功能修复线路 | 低拷贝基因线路设计; 表达负担负反馈线路; 毒性转录因子自负反馈; 生长速率补偿调控 | 基因组单拷贝整合的TetR-LacⅠ toggle switch[ 负担敏感phtpG1控制CRISPR/dCas9抑制的负反馈控制[ 转录因子CymR的自抑制诱导系统设计,减弱生长抑制毒性[ SpoTH元件降低ppGpp含量,维持生长速率恒定[ | ||
扰动噪声屏蔽 | 目的基因表达控制 | 稳定基因拷贝数变异; 组合iFFL/负反馈线路 | TALE设计线性抑制功能,稳定启动子表达受拷贝数影响[ rtTA-LacI/miR-FF3设计iFFL,排除转染量影响[ tTA-miR-FF4的iFFL与负反馈,组合控制[ | |
积分反馈控制线路 | σ/anti-σ; sense/anti-sense mRNA | SigW-RsiW的σ/anti-σ互作设计积分反馈控制[ tTA sense/anti-sense mRNA互作设计反馈控制[ | ||
鲁棒性功能拓扑发掘 | 基于拓扑约束的线路构建与扰动测试 | 基于拓扑穷举理论计算结果,T7 RNAP与CRISPR/dCpf1设计负反馈耦合线性弱自激活的基因线路,在输入信号改变、拓扑参数变异及底盘生理条件等进行系统扰动下均可实现RPA功能[ |
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